Minimally Invasive Treatment in NSCLC - The Japanese Experience and Approach -

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1 Minimally Invasive Treatment in NSCLC - The Japanese Experience and Approach - Masahiro Tsuboi, M.D., Ph.D. Group Chair, Lung Cancer Surgical Study Group in Japan Clinical Oncology Group (JCOG), Associate-Professor, Department of Thoracic Surgery & Oncology, Tokyo Medical University & Hospital Chief, Department of Thoracic Surgery, Kanagawa Cancer Center Surgical Outcome for NSCLC in Japan Stage TNM Clinical-s. (1994) 5 year survival rate (%) Clinical-s. (1999) Patho.-s. (1994) Patho.-s. (1999) IA T1N0M IB T2N0M IIA T1N1M IIB IIIA IIIB T2N1M0 T3N0M0 T3N1M0 TanyN2M0 TanyN3M0 T4NanyM IV TanyNanyM Asamura H, et al. JTO 2008 What was happened in the past decade? Improving of the perioperative care Dry side management No blood transfusion. Changing of the distribution on the histrologic type The increase of the adenocarcinoma (c.f.; Sq; decreasing) The pathological definition of the non-invasive adenocarcinoma; Noguchi classification. The introduction of the CT-screening in clinical practice (since 1994??) More smaller lesion was detected? Adjuvant therapy?? etc.. The changes of the number of the patients with ct1 (< 2cm)N0 NSCLC in TMU; '82-'84 '85-'87 '88-'90 '91-'93 '94-'96 '97-'99 Cases;

2 Minimally Invasive Treatment= Limited Resections for Small-sized Lung Cancer: Present Status and Future Directions Historical background for limited resection Review of literature Possible candidates for limited resection Future directions Extent of Parenchymal Resection for Lung Cancer Anatomical lobectomy Lymph node dissection Pneumonectomy Lobectomy Cahan W, J Thorac Surg 1960;39:555 Sublobar resection for lung cancer? Pro and Con for Lob & Sub-Lob Resection for T1N0 NSCLC Wide wedge Segementectomy Lobectomy Sublobar resection (limited resection) El-Sherif et al. Ann Thorac Surg 2006; 82:

3 Pro and Con for Lob & Sub-Lob Resection for T1N0 NSCLC; recent series Risk & Benefit balance Lob vs. SEG-WWR based on JCOG0201 data First author, year, [reference] Study period Number of patients Type of resection 5-year survival (or other as specified). Significance Lobectomy Segment. WWR Okada 2006 Okumura Lobectomy 89.1% 305 Segmentectomy or wedge 1241 Lobectomy 144 Segmentectomy 89.6% pt1n0m0 </= 2 cm in diameter, (excluding large cell carcinoma): 81% > 2 cm: 78% pt1n0m0 </= 2 cm in diameter, (excluding large cell carcinoma): 83% > 2 cm: 58% NS NS for tumors </= 2 cm S for tumors > 2 cm (p = 0.057) No. of pts Mortality 4 (0.7%) 0 0 Morbidity 27 (4.8%) 0 3 (5.8%) Ope. Time 175 m m. 93 m. Bleeding 78.5 ml 90 ml 10 ml Trans. blood 2.1% 1.9% 1.9% Lobectomy vs Limited Resection for T1N0 NCLC: Summary So far lobectomy is a standard mode of resection for stage I lung cancer. The mobidity and mortality for lobectomy is tolerable for most of the patients. Many retrospective studies are suggesting the equivalent efficacy of limited resection for stage I lung cancer, especially new T1a; 2cm or less in size. Are these results applicable for the present-day T1N0 populations? 3

4 High-reso. CT-era tumors vs. LCSG-era tumors: Differences in Tumor Populations GGO (ground glass opacity) GGO Recognized on high-resolution CT Localized or focal lesion Mild (moderate) increase of CT density, which do not obscure lung structures Non-solid GGO Part-solid (mixed) GGO 4

5 AAH (atypical adenomatous hyperplasia) BAC (bronchioloalveolar carcinoma) Solid nodule Invasive adenocarcinoma 5

6 Radiological-Pathological Correlation Solid component of GGO represents the feature of invasive growth. Pathology-CT Correlation Non-solid GGO AAH (atypical adenomatous hyperplasia) BAC (bronchioloalveolar carcinoma) Part-solid GGO BAC (bronchioloalveolar carcinoma) Adenocarcinoma with mixed subtypes (invasive) Solid Adenocarcinoma with mixed subtypes (invasive) Prognostic Significance of the Size of Central Fibrosis Prognosis of GGO-BAC tumors: Sakurai H et al. Am J Surg Pathol 2004; 28: Suzuki K, Yokose T. Ann Thorac Surg

7 Characteristics of GGO-BAC 1. Female predominance 2. No history of tobacco smoking 3. Multicentricity 4. Indolent nature of non-solid GGO Results of resection for GGO lesion(s) Outcome of resection for GGOs Authors Year Journal No. Pt Methods Jang 1996 Radiology Prognostic factors Focal area of GGO Prognosis Not reported Aoki 2001 Radiology 127 3cm Dimension GGO > % Kodama 2001 Lung Cancer 104 2cm Visual GGO > % Takamochi 2001 JTCVS 269 Ad TDR TDR & CEA 100% Kim/Johkoh 2001 AJR 224 3cm Ad - GGO extent Not reported Matsuguma 2002 JTCVS 111 cia Visual GGO > % Takashima 2002 Lung Cancer 64 2cm CT GGO > % Suzuki 2002 ATS 69 cia Ad Dimension GGO > 50% 100% Okada 2003 ATS 167 3cm Ad TDR TDR > % Ohde 2003 Lung Cancer 98 3cm Ad Dimension GGO > 50% 100% SAME SIZE, BUT NOT SAME CANCER (different stage of tumor progression) Sub-solid GGO Solid Adenocarcinoma 7

8 BASIC STRATEGY What Should Be the Intervention for GGOs? Indolent cancer (tumor) Careful watching Non-invasive cancer Minimally-invasive cancer Limited resection Invasive cancer Radical resection Factors Affecting the Strategy STRATEGY for Management of GGOs GGOs Character of lesion (non-solid vs. solid GGO) Size Location Disappear Non-solid Follow-up, obligation for 3 months 15>=Size F/U Inner Size>15mm Lobectomy/ Segmentectomy Outer WW Inner 15>=Size Lobectomy/ Segmentectomy Part-solid Outer Segmentectomy/ WW Size>15mm Lobectomy* * If frozen diagnosis suggests invasive feature, lobectomy may be performed. 8

9 Intervention for GGO-BACs Part-solid, Lobectomy 1.Non-solid GGO: mm > Careful Watching by HI-RESO CT mm < Wide wedge/segmentectomy 2.Part-solid GGO: mm > Segmentectomy/Wide wedge mm < Lobectomy (Segmentectomy) 50% (solid part) < Lobectomy *In case of inner location, lobectomy is recommended. Non-solid, Lobectomy Technical issues of Limited Resection 9

10 Pro & Con for Lob vs. Limited Resection for T1N0 NCLC Easy vs. Difficult Location for Limited Resection The intraoperative decision of the surgical margin is very important. Basic strategy for Segmentectomy Typical segmentectomy Critical issues; How to manage the intersegmental vein How to decide surgical margin? 10

11 Convenient Segmentectomy Radical segmentectomy - 1? Radical Segmentectomy - 2 Wide Wedge resection 11

12 How to make intersegmental faces? What is the most suitable procedure for preserving lung function? Stapling vs. Direct dividing Which is the prior procedure for the preservation of the postoperative pulmonary function? 術後肺機能 エアリークの遷延 コスト (stapler vs. Taco) Technical standardization and Consensus for Sublobar resection should be needed soon. ESTS is considering this project as the postgraduate course in Non-surgical approach as Minimally Invasive Tx. STS/AATS/ACOSOG?? 12

13 New Possibilities for GGOs or small-sized NSCLC Other than Surgery Radiation therapy SBRT, Radiosurgery Ablations Background Japanese investigators reports; equivalent to surgery? -many censored cases/insufficient f/u -pts selection/more peripheral lesions -many post hoc subgroup analyses We do NOT have prospective data in operable pts with T1N0M0 NSCLC. RFA, Microwave Cryotherapy Onishi et al. JCOG 0403 A PHASE II STUDY OF STEREOTACTIC BODY RADIATION THERAPY IN PATIENTS WITH T1N0M0 NON-SMALL CELL LUNG CANCER To evaluate the safety and efficacy of SBRT for T1N0M0 NSCLC? SBRT as a standard care in medically inoperable pts? SBRT as a treatment option in operable pts Primary endpoint, 3-year overall survival Sample size, 165 (started on 20/07/2004) operable, 65 inoperable, 100 JCOG 0403 A PHASE II STUDY OF STEREOTACTIC BODY RADIATION THERAPY IN PATIENTS WITH T1N0M0 NON-SMALL CELL LUNG CANCER Eligibility Criteria -Pathologically proven NSCLC -T1N0M0 -Medically inoperable or operable (refused surgery) -PS 0-2 -PaO2 > 60 torr -FEV1.0 > 700 ml -Signed informed consent Operability is judged by surgeons 13

14 JCOG 0403 A PHASE II STUDY OF STEREOTACTIC BODY RADIATION THERAPY IN PATIENTS WITH T1N0M0 NON-SMALL CELL LUNG CANCER Treatment MV X rays -48 Gy in 4 fractions over 4-8 days -prescribed to the isocenter -heterogeneity corrected dose -algorithm, pencil beam; NOT superposition -CTV = GTV -PTV = ITV + 5 mm -MLC margin, 5 mm static beams or multiple arc beams > 400 deg Future Directions Kid s park 14

15 BASIC STRATEGY for Surgery in small-sized NSCLC Non-invasive cancer Minimally-invasive cancer Limited resection Critical issues Lob vs. SEG-WWR Really less invasive? Operative time, Hospital stay Morbidity/mortality Invasive cancer Radical resection Really preserving lung function? Short-time function vs. Long-term function Clinical trials for Minimally Invasive approach in Japan JCOG/WJOG trials for stage IA (T1aN0M0) NSCLC 0%<Solid<25% One-arm, wide wedge resection (phase II) What is a standard procedure for ct1an0m0 NSCLC? 25%<Solid<100% Lobectomy vs. Limited (Seg) (phase III) 15

16 Study 1: JCOG0804/WJOG4507L; Phase II Trial of Limited Resection (Wide wedge resection) for Possible Early Adenocarcinomas (GGO Partsolid GGO) ; (Single-arm study) PI: Tsuboi M. Subject ---- Non-solid GGO or part-solid GGO Solid part < 25% Why one arm? Very few event (cancer-related death) to perform comparative study Intervention Wide Wedge resection Endpoint Recurrence-free survival rate at any site Sample size patients Study 2: JCOG0802/WJOG4607L; Phase III Randomized Trial between Lobectomy and Limited Resection for Small-sized carcinoma (Part-solid GGO Solid 2cm or Less ) Peripheral carcinoma, <=2 cm Negative hilar node Stratified factors; Institute, Gender, Histology (Ad vs, Non-ad), Solid or non-solid Non-inferiority design Randomize PI: Asamura H. Lobectomy Segmentectomy Endpoints: Primary: OS Secondary: pulmonary function Sample size: 1,100 CALGB Intergroup; Phase III Randomized Trial between Lobectomy and Sublobar Resection for Smallsized carcinoma Peripheral carcinoma, <=2 cm Negative hilar node Stratified factors; Tumor size, Histology (Sq vs. non-sq)?, Smoking status Non-inferiority design Randomize Lobectomy Since Sep PI: Altorki N Sublobar resection (segmentectomy/ wedge) Endpoints: Primary: DFS Secondary: OS, pulmonary function Sample size: 1,300 Patients Trial design Target number. / Entry period / follow-up Comparison of CALGB with JCOG0802/WJOG CALGB Peripheral small (2cm or less) NSCLC without pure GGO lesion Randomized phase III / noninferiority trial 1297 cases (908 cases after randomization) / 5 years / 3.25 years Standard arm Lobectomy Lobectomy Investigational arm Wedge resection or Segmentectomy JCOG0802/WJOG Peripheral small (2cm or less) NSCLC without non-invasive lung cancer on Chest CT-scan Randomized phase III / noninferiority trial 1100 cases / 3 years / 5 years Segmentectomy Primary endpoint Progression Free Survival Overall survival Secondary endpoints OS, Local recurrence rate, Distant recurrence rate, Postope. pulmonary function at 6 months (FEV1.0, FVC) Postope. pulmonary functions at 3 months and 1 year, DFS, Local recurrence rate, Adverse events, hospitalization, chest drainage term, Operative time, bleeding amount, number of autostaplers 16

17 Eligibility criteria (2 nd registration during operation) Exclusion criteria Stratified factors Postoperative follow-up Comparison of CALGB with JCOG0802/WJOG CALGB No lymph node metastasis by frozen diagnosis: Right (#4, #7, #10), Left (#5, #6, #7, #10) Pure GGO, Carcinoid tumor (1) Tumor size (1.5 > vs. 1.5 cm=<) (2) Smoking history (3) Histology CT; 8, 12 months, and then every year JCOG0802/WJOG Frozen; not mandatory, No noncurative factor, such as malignant pleural effusion and dissemination, Both Lobectomy and Segmentectomy are possible Carcinoid tumor (1) Institute (2) Hisotology (adeno. Vs. nonadeno.) (3) Gender (4) Age (70 y.o.>, vs. 70=<) (5) Thin-slice CT findings (solid vs. non-solid) CT: every 6 months Conclusions Many retrospective studies are suggesting the equivalent efficacy of limited resection for stage I lung cancer. Prospective clinical trials are on going. New standard approach of small-sized NSCLC will be established. Technical consensus for sub-lobar resection should be needed in the worldwide. Thank You for Your Attention. 17

18 Reports on the Comparison btwn Lobectomy & Limited Resection for T1N0 NCLC: A Lung Cancer Study Group Back-up Authours Study No. of limited No. of Survival design resection lobectomy difference Hoffmann and Ransdell (1980) RS 33 (W) 40 a NS Read et al (1990) RS 113 (IO7S+6W) 131 NS (CSS) Date et al (1994) MPS 16 (6S+10W) 16 Lobectomy better Warren and Faber (1994) RS 66 (S) 103 Lobectomy better Harpole et al (1995) RS 75 (W) 193 NS (CSS) LCSG (1996) RCT 122 (82S+40W) 125 NS Kodama et al (1997) RS 46 b (W) 77 NS Landreneau et al (1997) RS 102 (W) 117 NS Pastorino et al (1997) RS 53 (S+W) 367 NS Kwiatowski et al (1998) RS 58 (S+W) 186 c Lobectomy better Okada et al (2001) RS 70 (S) 139 NS Koike et al (2003) RS 74 (60S+14W) 159 NS Campione et al (2004) RS 21 (S) 100 NS Keenan et al (2004) RS 54 (8) 147 NS Lobectomy vs. Limited Resection for T1N0 NSCLC: A Lung Cancer Study Group Ann Thorac Surg 1995; 60: Pts. randomized 247 Pts. Eligible for analysis Lobectomy vs. Limited Resection for T1N0 NSCLC: A Lung Cancer Study Group Ann Thorac Surg 1995; 60: Peripheral carcinoma on CXR, <=3 cm Negative hilar node Randomize Lobectomy Limited resection Endpoints: Primary: OS Secondary: pulmonary function Sample size: 80 deaths and 70 recurrences to occur with a power of.90 to detect a 1.8 fold difference in median survival Lobectomy (125) vs. Limited (122) (82, Seg; 40, Wedge) Survival was improved in the Lob group but was of borderline statistical significance. Local-regional recurrence rate showed a 3-fold increase with limited resection. 25% of pts. of clinically staged as T1N0 were found to have positive mediastinal LN. 18

19 Lobectomy vs Limited Resection for T1N0 NSCLC: A Lung Cancer Study Group Ann Thorac Surg 1995; 60: Lobectomy vs Limited Resection for T1N0 NSCLC: A Lung Cancer Study Group Ann Thorac Surg 1995; 60: Time to Death (p=0.088) Time to Recurrence (p=0.016) CONCLUSION: Lobectomy with systematic hilar/mediastinal LN sampling/dissection should remain the standard surgical treatment for clinical T1N0 tumors. Lobectomy vs Limited Resection for T1N0 NSCLC: A Lung Cancer Study Group Study itself: Slow accrual: 276 pts. in almost 7 years Survival difference: borderline significance Enough statistical power? No available data regarding lung function Superiority design From present view point: Old study Ann Thorac Surg 1995; 60: Critiques: Earlier, smaller cases, not included Lobectomy vs. Limited Resection for T1N0 NCLC: A meta-analysis of 14 comparative studies Nakamura H et al. Br J Cancer 2005; 92: A meta-analysis of 14 comparative studies between lobecotmy and limited resection for stage I lung cancer 13 retrospective studies and 1 randomized study Stages, IA only (9), IA+IB (5) Endpoint, a combined survival difference at 1, 3, and 5years 19

20 Lobectomy vs Limited Resection for T1N0 NCLC: A meta-analysis of 14 comparative studies Results: Nakamura H et al. Br J Cancer 2005; 92: Lobectomy vs Limited Resection for T1N0 NCLC: A meta-analysis of 14 comparative studies Nakamura H et al. Br J Cancer 2005; 92: YS; 0.7% 3YS; 1.9% 5YS; 3.6% Conclusion: While survival after lobectomy was slightly better than that after limited resection at 1, 3, and 5 years postoperatively, the differences were not statistically significant. Lobectomy vs Limited Resection for T1N0 NCLC: A meta-analysis of 14 comparative studies Nakamura H et al. Br J Cancer 2005; 92: Cautious note: Application of meta-analysis method for retrospective studies Heterogeneity among studies (indication for surgery) Publication bias Results of careful watching 20

21 Follow-up Study of GGO Lesions for at Least 6 Months ( ): N=136 Fate of GGOs According to CT Appearance ( ): N=136 (1) Demographic data SEX: male (50, 36.8%), female (86, 61.2%) AGE: 62.1 years (35-81) FOLLOW-UP PERIOD: 29.9M ( ) (2) Type of lesion Non-solid 97 (71.3%) Part-solid or SC 32 (23.5%) Solid 7 ( 5.2%) (3) Size 1cm or less 80 (58.8%) More than 1cm 56 (41.2%) (4) History of previous lung cancer Yes 14 (10.3%) No 122 (89.7%) Disappeared Non-solid (n=97) Unchanged Part-solid (n=14) Increased Semi-solid (n=18) Solid (n=7) Fate of GGOs According to History of Previous Lung Cancer ( ): N=136 Fate of GGOs According to Size ( ): N=136 Disappeared 90 % Unchanged Hx of lung tum or Increased No prior surgery Disappeared Unchanged cm or less Increased M ore than 1 cm P <

22 Predictors of Increase in Size Multivariate analysis Summary so far Probability OR 95% CI Tumor size (mm: continuous variable) Shape of tumor (irregular vs round) Sub-centimeter lung tumors showing non-solid GGO on HRCT tend to be stable in size. 2. Shape of tumor and tumor size were significant predictors for increase in size of GGO tumors. 3. GGO tumors found in patients who had a history of lung cancer tend to grow up fast. % PAPILLARY ADENOCARCINOMA BY MAJOR SUBTYPE A Natural History of Peripheral Adenocarcinomas (Well differentiated histology) Promine nt Subtype Kim et al N=36 Takano et al N=66 Nakamura et al N=130 Motoi et al N=100 Acinar 5 (14%) 18 (27%) 5 (4%) 30 (30%) PURE GGO Complex GGO with solid component Papillary 17 (47%) 30 (45%) 62 (48%) 37 (37%) BAC 7 (19%) 9 (14%) 15 (12%) 7 (7%) Solid 7 (19%) 5 (8%) 21 (16%) 25 (25%) Kim YH et al: ClCa Res 10: 7311, 2004;Takano T et al: JCO 23:6829, 2005 Nakamura Y: Ca Sci 98: INDOLENT! Solid tumor with vascular and bronchial convergence Solid tumor 22

23 Does GGO Grow? Yes. GGO, enlarged Feb 7/ 2001 July 7/ 2003 Jan 21/ 2001 Jan 15/

24 Does GGO Always Grow? No, not always. Feb 5/ 1998 Aug 4/